Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. Efforts continue to investigate factors which affect insulin action and secretion. We have also investigated the portion of glucose uptake that is non-insulin mediated. Using a large dataset, we were able to reproduce previous estimates of rates of non-insulin mediated glucose uptake (NIMGU). We also found that NIMGU was positively related to adiposity, and that it increased with worsening glucose tolerance. We also investigated parental effects on risk factors for diabetes. We found that offspring of fathers with early onset (<35 years of age) have less body fat and lower insulin secretion, despite similar measures of insulin action. These data indicate a paternal imprinted effect in these individuals. We are continuing to investigate additional factors which control insulin secretion and insulin action. Individuals who are undergoing bariatric surgery using the following techniques: Roux-en-Y gastric bypass, laporoscopic band, or gastric sleeve will undergo measures of insulin action, insulin secretion and meal tests prior to and one month following the surgery. This study will investigate how by-pass of the duodenum and specific areas of the stomach influence insulin action and secretion as well as their affect on gastrointestinal hormones. Adiposity is also a pro-inflammatory state and such inflammation may affect insulin action directly. We have previously investigated the role of recently identified adipose tissue macrophages and their associations with obesity and insulin action. Adipose tissue macrophages increased with adiposity, and were negatively associated with insulin action, although not independent of adiposity. However, markers of macrophage activation in adipose tissue (specifically plasminogen activator inhibitor-1 (PAI-1) were associated worsening insulin action independent of body fat, indicating a role for macrophage activation in insulin resistance. Previous predictors of weight gain based on this study have included, higher respiratory quotient, higher insulin mediated glucose uptake, lower free T3, and relatively lower energy expenditure. Variance in adiposity within the Pima Indian population is largely due to genetic varation as well. Melanocortin 4 receptor variants are the most common monogenetic cause of obesity. Functional melanocortin 4 receptor variants have been identified in the Pima Indian population, including a novel variant predicting a STOP codon. These variants are associated with increased adiposity, but also with lower energy expenditure. This is the first demonstration of an association between a monogenic form of obesity and lower metabolic rate in humans. We have also identified that markers of inflammation, including white blood cell count but also importantly adipose tissue markers are negatively associated with energy expenditure. This indicates that the increasing inflammation seen with increased adiposity may also serve as a brake to further weight gain.